Orthopedic surgeries to reconstruct and replace joints are increasingly in demand due to an aging population and improvements in materials and techniques. However, postsurgical infections are also of increasing concerns and are difficult to treat, often requiring revision surgeries that add to patient suffering and medical costs. This problem is particularly acute in shoulder arthroplasty, where robust aseptic protocols are not effective in preventing infections due to Cutibacterium (formerly Propionibacterium) acnes, an opportunistic pathogen enriched in sebum-rich sebaceous follicles that are found in abundance in the shoulder area. Dermalytica is developing first-in-class antimicrobials that target pathogenic bacteria without impacting healthy microbiota. A novel and diverse class of mycobacteriophage-encoded lytic enzymes can selectively and rapidly lyse C. acnes, the bacterial culprit in acne. Dermalytica is developing these lytic enzymes as selective topical antimicrobials that can penetrate sebaceous follicles as acne treatments, and the target product profile is similar to that for prevention of shoulder arthroplasty postsurgical infections. We propose to obtain proof-of-concept data on screening a panel of diverse lytic enzymes for their ability to kill a broad range of C. acnes clinical isolates obtained from shoulder surgeries that have been fully sequenced and molecularly characterized. Success in the proposed studies will enable a comprehensive screen for suitable candidates to undergo preclinical development as a first-in- class prophylactic antimicrobial to prevent shoulder arthroplasty infections and address this acute unmet medical need.